Apathy is a syndrome characterized by a primary lack of motivation and is manifested as a lack of effort and productivity, dependence on others for structuring daily activities, loss of interest in new experiences, lack of concern for one's problems, and lack of response to positive or negative events. Apathy is different from depression. It is more common and more severe in patients with PD compared to healthy subjects, those with osteoarthritis, and other movement disorders.
Almost by definition, apathy has a direct impact on the overall level of handicap, as it reduces participation in age appropriate activities above and beyond that due to the motor impairment. It contributes significantly to caregiver burden, and has negative implications for treatment and long-term outcome. There is no known cure for this potentially disabling syndrome and controlled clinical trials that focus on apathy have not been reported.
Apathy has been consistently thought of as a defect of 2 interconnected areas in the brain called frontal cortex and the anterior cingulate cortex (ACC), with their connections to the basal ganglia--the part of the brain involved in Parkinson's disease.
Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive tool that can 'stimulate' specific areas of the brain surface through the skull which, in turn, induces changes in behavior. For example, rTMS have been reported to improve depression because of its modulatory effect on the fronto-cingulate system (the frontal cortex and the ACC circuitry). Studies have shown that rTMS of the left MDLFC modulates the blood flow response in the ACC. We therefore hypothesize that high-frequency rTMS of the left frontal cortex will also improve apathy in PD.
We plan to conduct a single-center, double-masked, placebo-controlled, randomized study of fixed-dose, high-frequency rTMS in 36 PD patients experiencing apathy. The primary outcome measure will be the improvement in a standard apathy scale: the modified Apathy Evaluation Scale (AES). Other outcome measures will include changes in: other apathy, depression and disability scales, the frontal cortex and ACC activation via functional magnetic resonance imaging (fMRI), and frequency of adverse events. Patients will receive high frequency rTMS stimulation (or placebo) daily for 10 days over a two-week period and followed at baseline, day 10, and months one and three post rTMS.
Final Outcome
Apathy is a common neuropsychiatric feature of PD without a known reliable treatment. While repetitive transcranial magnetic stimulation (rTMS) improves depression, its effects on apathy are unknown. We recruited 24 patients with PD experiencing mixed apathy/depression (N=13) or pure apathy (N=11) from the UF Movement Disorders Center. In a 2:1 randomization, patients underwent rTMS (N=16) or sham treatment (N=8). Apathy, depression and motor scales were administered prior to, immediately following, and one and three months after treatment. Fixed dose, high frequency rTMS (or sham stimulation), was delivered over the left prefrontal area of the scalp daily for 10 days over a 2-week period. Our patients did not successfully guess their randomization, and pain ratings did not differ between sham and rTMS. Immediately following any treatment, significant improvements in apathy, depression, motor functioning and quality of life were found. No differences on any of these measures between sham and rTMS groups, or between pure apathy and mixed apathy-depression groups were noted. Analyses of the three-month follow-up period revealed that these gains were maintained for apathy, but not for depression or motor functioning. Patients reported multi-domain behavioral improvements following both real and simulated rTMS. Results provide support for brief, daily behavioral activation intervention for apathy, but do not demonstrate a unique effect of rTMS.